Receptor tyrosine kinases (RTKs) have been implicated in cellular signaling pathways that control various cellular functions, including cell division, growth, metabolism, differentiation and survival, through reversible phosphorylation of the hydroxyl groups of tyrosine residues in proteins. Extracellular signals are transduced via activation of the cell surface receptors, with amplification and propagation using a complex choreography of cascades of protein phosphorylation and protein dephosphorylation events to avoid uncontrolled signaling. These signaling pathways are highly regulated, often by complex and intermeshed kinase pathways where each kinase may itself be regulated by one or more other kinases and protein phosphatases. The biological importance of these finely tuned systems is such that a variety of cell proliferative disorders have been linked to defects in one or more of the various cell signaling pathways mediated by tyrosine or serine/threonine kinases.
Receptor tyrosine kinases (RTKs) catalyze phosphorylation of certain tyrosyl amino acid residues in various proteins, including themselves, which govern cell growth, proliferation and differentiation. Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane tyrosine kinase ubiquitous among fetal and post-natal cell types.
The IGF signaling axis is made up of multiple ligands (IGF-1, IGF-2 and Insulin), at least six high affinity ligand binding proteins and proteases, multiple receptors (IGF-1R & IGF-2R, IR and IRR), and many other down stream signaling proteins (Pollak, M N et al., Nature Reviews Cancer (2004) 4(7):505-518). The structure and function of the IGF-1R has been reviewed by Adams et al., Cell. Mol. Life Sci. (2000) 57:1050-1093 and Benito, M et al., Int J Biochem Cell Biol (1996) 28(5):499-510. The receptor is activated by the ligands IGF-1 and IGF-2, which are mitogenic proteins that signal through the IGF-1R and IR in an endocrine, paracrine or autocrine manner. Activation of the IGF-1 receptor tyrosine kinase elicits cellular responses which include cellular proliferation and protection of cells from apoptosis. (Id.) Over expression of IGF-1R leads to malignant transformation of cultured cells, while down regulation can reverse the transformed phenotype of tumor cells and potentially render them susceptible to apoptosis. (Id.)
There are two splice variants of the IR gene, the IR-β isoform which regulates glucose uptake and is expressed in liver, muscle and adipose tissue, and the exon 11 variant human insulin receptor isoform A (IR-A) binds IGF-2 with high affinity and promotes proliferation and protection from apoptosis (Sciacca L. Oncogene (2002) 21(54):8240-8250). IR-A is predominantly expressed in fetal tissue and malignancies and at this receptor, IGF-2 is more potent than insulin in stimulating cancer cell migration. (Sciacca, Oncogene (2002) supra). Insulin receptor-related receptor tyrosine kinase (IRR) has 79% homology with the kinase domain of IR and is expressed only in a few limited cell types (Dandekar, A A et al., Endocrinology (1998) 139(8):3578-3584).
IGF-1R is a hetero-tetrameric, transmembrane, cell surface receptor tyrosine kinase. (Benito, Int J Biochem Cell Biol (1996)) An IGF-1 binding domain is part of the extracellular alpha-chain of IGF-1R, whereas the intracellular beta-chain contains the tyrosine kinase domain. Three tyrosine residues represent autophosphorylation sites, specifically Tyr1131, Tyr1135, and Tyr1136, within the activation loop of the IGF-1R beta catalytic domain (Li, W et al., J. Biol. Chem. (2006) 281(33):23785-23791). Phosphorylation of all three is required for full receptor activation, and precedes phosphorylation of juxtamembrane tyrosines and carboxy terminus serines. The insulin receptor has three similar autophosphorylation sites on the activation loop and juxtamembrane region. Activation and autophosphorylation results in the recruitment of multiple docking proteins and the generation of intracellular signaling (Benito, Int J Biochem Cell Biol (1996)). Once activated, IGF-1R and IR can phosphorylate or interact directly with a number of intracellular protein substrates, including IRS-1, IRS-2, Grb2, Grb10, Grb14, Shc, SOC, 14.3.3, FAK, or indirectly with other proteins like PI3K and MAPK (Benito, M et al. Int J Biochem Cell Biol (1996) 28(5):499-510) (Brown, G C et al., Biochem. J (1992) 284:1-13; Bruning, J C et al., Mol. Cell (1998) 2(5):559-569). Focal adhesion kinase (FAK) is of particular interest because of its role as a regulator of cell survival, proliferation, migration and invasion. FAK is activated by growth factor receptors such as IGF-1R, by binding through its N-terminal domain and autophosphorylation at Tyr397. Activated or over expressed FAK is common in a wide variety of cancers, and may play a role in human carcinogenesis (van Nimwegen, M J et al., Biochem. Pharmacol. (2007) 73(5):597-609).
In addition to its role in cancers, the IGF receptor plays important and diverse roles in growth and development (Benito, M et al. Int J Biochem Cell Biol (1996) 28(5):499-510). IGF-1R has been implicated in several metabolic, and immunological diseases (Walenkamp, M J et al., Horm. Res. (2006) 66(5):221-230; Kurmasheva, R. T et al., Biochim. Biophys. Acta—Rev on Cancer (2006) 1766(1):1-22; Bateman, J M et al., Cell. Mol. Life Sci. (2006) 63(15):1701-1705, LeRoith, D, et al., Can. Lett. (2003) 195:127-137 and Samani A, et al., Endocrine Reviews 28(1):20-47.)
The role of the IGF/IGF-1R signaling system in cancer has been thoroughly examined over the last 15 years. In particular, the implication of IGF-1R in human cancer stems from its roles in stimulating mitogenesis, mobility and metastasis and in protecting against apoptosis. (Kurmasheva, Biochim. Biophys. Acta (2006).) Interest has grown with the understanding that in addition to its antiapoptotic and mitogenic roles, IGF/IGF-1R signaling seems to be necessary for the establishment and continuation of a transformed phenotype. It has been well established that constitutive activation or over expression, often results in non-adherent cell growth, even under serum depleted conditions in vitro, and is associated with the formation of tumors in nude mice. (Kaleko M et al, Mol Cell Biol. (1990) 10(2): 464-473). Perhaps even more importantly, it has been firmly established that cells, in which the gene encoding for IGF-1R has been deactivated, are totally resistant to transformation by agents which are normally capable of immortalizing normal cells, such as over expression of PDGFR or EGFR, the T antigen of the SV40 virus, the E5 protein of bovine papilloma virus, and activated ras. (DeAngelis T et al., Cell. Physiol. (1995) 164( ):214-221; Coppola D et al., Mol. Cell. Biol. (1994) 14(7):4588-4595; Morrione A J, Virol. 1995 695300-5303; Sell C et al., Mol. Cell. Biol. (1994) 14(6):3604-3612; Sell C et al., Proc. Natl. Acad. Sci. USA (1993) 90(23):11217-11221). Thus, IGF-1R has been identified as the major survival factor that protects from oncogene induced cell death (Harrington et al., EMBO J. (1994) 13( ):3286-3295). IGF-1R is expressed in a large number and variety of tumors and the IGFs amplify the tumor growth through their interaction with the receptor. Evidence supporting the role of IGF-1R in carcinogenesis can be found in studies using monoclonal antibodies directed towards the receptor which inhibit the proliferation of numerous cell lines in culture and in vivo (Arteaga C et al., Cancer Res. (1989) 49(22):6237-6241; Li et al., Biochem. Biophys. Res. Com. (1993) 196(1):92-98; Scotlandi K et al., Cancer Res. (1998) 58(18):4127-4131). Dominant negative IGF-1R is capable of inhibiting tumor proliferation (Jiang et al., Oncogene (1999) 18(44):6071-6077). The IGF signaling axis is implicated in various tumor types including:    breast cancer (Surmacz, J. Mammary Gland Bio. Neoplasia (2000) 5(1):95-105, LeRoith, Can. Lett. (2003) and Artega, Cancer Res. (1989)),    sarcoma including soft-tissue sarcoma (e.g., cartilage sarcoma, connective tissue (chondrosarcoma) and fibrous matrix (fibrosarcoma)) and hard bony sarcomas (e.g., Ewing's sarcoma, osteosarcoma and giant cell tumor of bone) (Scotlandi, Cancer Res. (1998)    lung cancer, including non-small cell and small cell lung carcinomas and mesotheliomas (Jiang, Y et al., Oncogene (1999) 18:6071-6077 and LeRoith, Can. Lett. (2003),    prostate cancer (Djavan et al., World J Urol. (2001) 19(4):225-233; O'Brien et al., Urology (2001) 58(1):1-7 and LeRoith, Can. Lett. (2003)),    colorectal cancer (Guo et al., Gastroenterology, 1992, 102, 1101-1108; Durai, R et al., Int. J Colorectal Dis. (2005) 20(3):203-220 and LeRoith, Can. Lett. (2003)),    renal cancer (Kellerer M. et al., Int. J. Cancer (1995) 62(5):501-507),    pancreatic cancer (Bergmann, U et al., Cancer Res. (1995) 55(10):2007-2011),    hematologic cancers, including lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, myelodysplastic syndromes, (Zumkeller W et al., Leuk. Lymph (2002) 43(3):487-491; and Qi, Ann Hematol. (2006) 85:95-101),    neuroblastomas (Zumkeller, W et al., Horm. Metab. Res. 1999, 31, 138-141),    primary CNS tumors including: astrocytomas (also known as “gliomas”) including glioblastoma multiforme; meningiomas and medulloblastomas (Zumkeller, W et al., Mol. Pathol. (2001) 54(4):227-229, Del Valle L, et al., Clin. Cancer Res. (2002) 8:1822-1830 and Trojan et al., Proc. Natl. Acad. Sci. USA (1992) 89:4874-4878),    secondary CNS tumors, i.e., metastases in the central nervous system (e.g., the brain), of a tumor originating outside of the central nervous system (Burfeind P, et al, PNAS (1996) 93:7263-7268),    head and neck cancer (Wu X., et al, Clin. Cancer Res. (2004) 10:3988-95),    thyroid cancer (Vella V et al., J. Clin. Endocrinol. Metab. (2002) 87:245-254; Vella V et al., Mol. Pathol. (2001) 54(3):121-124),    hepatocarcinoma (Alexia, C et al., Biochem. Pharmacol. (2004) 68:1003-1015),    ovarian cancer, vulval cancer, cervical cancer, endometrial cancer,    testicular cancer (Neuvians T P, et al, Neoplasia (2005) 7:446-56),    bladder cancer (Zhao H., et al, J. Urology (2003) 169:714-717),    esophageal cancer (Sohda M, et al, Anticancer Research. (2004) 24:3029-3034),    gastric cancer (Jiang, Y, et al, Clinical & Experimental Metastasis (2004) 21:755-64),    buccal cancer, cancer of the mouth, (Brady G et al., Int. J. of Oral & Maxillofacial Surg. (2007) 36:259-62).    GIST (gastrointestinal stromal tumor) (Trent J C, et al, Cancer. (2006) 107:1898-908), and    skin cancer including melanoma (Yeh A H, et al, Oncogene. (2006) 25:6574-81).
Thus, in virtually all types of human cancers there is a strong association between dysregulation of IGF signaling and carcinogenesis (Bohula E A et al., Anticancer Drugs (2003) 14(9):669-682). Inhibition of IGF-1R and/or IR expression or function has been shown to block tumor growth and metastasis and also enhance sensitivity to other anti-neoplastic therapies, including cytotoxic drugs and radiation. (Bohula, Anticancer Drugs (2003).
Other receptor tyrosine kinases, the ErbB family tyrosine kinases, includes EGFR, ErbB2, ErbB3 and ErbB4. Aberrant activity in the ErbB family kinases has been implicated in a range of hyperproliferative disorders including psoriasis, rheumatoid arthritis, bronchitis and several cancers. The biological role of ErbB family RTKs and their implication in different disease states has been widely discussed (Ullrich, A., et al., Cell (Apr. 20, 1990) 61: 203-212; Aaronson, S., Science (1991) 254:1146-1153; Salomon, D., et al., Crit. Rev. Oncol./Hematol. (1995) 19:183-232; Woodburn, J. R., Pharmacol. Ther. (1999) 82: 2-3, 241-250; Normanno, N., et al., Curr. Drug Targets (2005) 6:243-257; and Hynes, N. et al., Nat. Rev. Cancer (2005) 5:341-345). In particular, elevated EGFR activity has been implicated in non-small cell lung, squamous cell lung, breast, bladder, head and neck squamous cell, esophageal, gastric, colorectal, pancreatic, thyroid, glial, cervical and ovarian cancers (Salomon (1995) supra; Woodburn (1999) supra; Normanno (2005) supra; Hynes (2005) supra). Furthermore, overexpression and/or mutation of ErbB2 has been implicated in non-small cell lung, breast, ovarian, esophageal, gastric, colorectal, glial, pancreatic and cervical cancers (Salomon (1995) supra; Normanno (2005) supra; Hynes (2005) supra). A timeline of events pertaining to the role of the ErbB family kinases in cancer may be found in Gschwind, A., et al., Nat. Rev. Cancer (2004) 4:361-370. By virtue of the role played by the ErbB family kinases in these cancers and the relative success of inhibitors of these kinases in the clinic, it is widely acknowledged that inhibitors of one or more ErbB family kinases will be useful for the treatment of such cancers.
PCT Publication No. WO03/031446, published 17 Apr. 2003 to GlaxoSmithKline, recites antiviral compounds of the formula:
wherein:    p is 0, 1 or 2;    each R1 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR7, —OHet, —C(O)R9, —C(O)Het, —CO2R9, —C(O)NR7R8, —C(NH)NR7R8, —S(O)nR9, —S(O)2NR7R8, —NR7R8, —NR7Ay, —NHHet, —R10cycloalkyl, —R10Het, —R10OR9, —R10SO2NHCOR9, —R10NR7R8, cyano, nitro and azido; or            two adjacent R1 groups together with the atoms to which they are bonded form a C5-6 cycloalkyl or 5- or 6-membered heterocyclic group including 1 or 2 heteroatoms;        each R7 and R3 are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkenyl, —C(O)R9, —CO2R9, —C(O)NR9R11, —C(NH)NR9R11, —SO2R10, —SO2NR9R11, —R10cycloalkyl, —R10OR9 and —R10NR9R11;        each R9 and R11 are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, —R10cycloalkyl, —R10OH, —R10(OR10)w where w is 1-10 and —R10NR10R10;        each R10 is the same or different and is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl;        Ay is aryl;        Het is a 5- or 6-membered heterocyclic or heteroaryl group;            R2 is selected from the group consisting of H, alkyl and cycloalkyl;    n is 0, 1 or 2;    Y is N or CH;    R3 and R4 are the same or different and are each independently selected from the group consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, —OR7, —C(O)R7, —CO2R7, —SO2NHR9, —NR7R8, —NHHet and —NHR10Het;    q and q′ are the same or different and are each independently selected from the group consisting of 0, 1, 2 and 3; and    each R5 and R5′ are the same or different and are independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR7, —OAy, —OR10Ay, —OHet, —OR10Het, —C(O)R9, —C(O)Ay, —C(O)Het, —CO2R9, —C(O)NR7R8, —C(O)NR7Ay, —C(O)NHR10Het, —C(S)NR9R11, —C(NH)NR7R8, —C(NH)NR7Ay, —S(O)nR9, —S(O)2NR7R8, —S(O)2NR7Ay, —NR7R8, —NR7Ay, —NHHet, —NHR10Ay, —NHR10Het, —R10cycloalkyl, —R10Het, —R10OR9, —R10C(O)R9, —R10CO2R9, —R10C(O)NR9R11, —R10C(O)NR7Ay, —R10C(O)NHR10Het, —R10C(S)NR9R11, —R10C(NH)NR9R11, —R10SO2R9, —R10SO2NR9R11, —R10SO2NHCOR9, —R10NR7R8, —R10NR7Ay, —R10NHC(NH)NR9R11, cyano, nitro and azido; or            two adjacent R5 or R5′ groups together with the atoms to which they are bonded form a C5-6 cycloalkyl or aryl.        
PCT Publication No. WO2003/000689, published 3 Jan. 2003 to GlaxoSmithKline recites antiviral compounds of the formula:
wherein:    p is 0, 1, 2, 3 or 4;    each R1 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR7, —OAy, —OR10Ay, —OHet, —OR10Het, —C(O)R9, —C(O)Ay, —C(O)Het, —CO2R9, —C(O)NR7R8, —C(O)NR7Ay, —C(O)NHR10Ay, —C(O)NHR10Het, —C(S)NR9R11, —C(NH)NR7R8, —C(NH)NR7Ay, —S(O)nR9, —S(O)nAy, —S(O)nHet, —S(O)2NR7R8, —S(O)2NR7Ay, —NR7R8, —NR7Ay, —NHHet, —NHR10Ay, —NHR10Het, —R10cycloalkyl, —R10Ay, —R10Het, —R10O—C(O)R9, —R10O—C(O)Ay, —R10O—C(O)Het, —R10O—S(O)nR9, —R10OR9, —R10C(O)R9, —R10CO2R9, —R10C(O)NR9R11, —R10C(O)NR7Ay, —R10C(O)NHR10Het, —R10C(S)NR9R11, —R10C(NH)NR9R11, —R10SO2R9, —R10SO2NR9R11, —R10SO2NHCOR9, —R10NR7R8, —R10NR7Ay, —R10NHC(NH)NR9R11, cyano, nitro and azido; or            two adjacent R1 groups together with the atoms to which they are bonded form a C5-6cycloalkyl or a 5 or 6-membered heterocyclic ring containing 1 or 2 heteroatoms;        
each R7 and R8 are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —OR9, —C(O)R9, —CO2R9, —C(O)NR9R11, —C(S)NR9R11, —C(NH)NR9R11, —SO2R10, —SO2NR9R11, —R10cycloalkyl, —R10OR9, —R10C(O)R9, —R10CO2R9, —R10C(O)NR9R11, —R10C(S)NR9R11, —R10C(NH)NR9R11, —R10SO2R10, —R10SO2NR9R11, —R10SO2NHCOR9, —R10NR9R11, —R10NHCOR9, —R10NHSO2R9 and —R10NHC(NH)NR9R11;                each R9 and R11 are the same or different and are independently selected from the group consisting of H, alkyl, cycloalkyl, —R10cycloalkyl, —R10OH, —R10(OR10)w where w is 1-10 and —R10NR10R10;        each R10 is the same or different and is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl;        Ay is aryl;        Het is a 5- or 6-membered heterocyclic or heteroaryl group;            R2 is selected from the group consisting of halo, alkenyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR7, —OAy, —OHet, —OR10Het, —S(O)nR9, —S(O)nAy, —S(O)nNR7R8, —S(O)nHet, —NR7R8, —NHHet, —NHR10Ay, —NHR10Het, —R10NR7R8 and —R10NR7Ay;    n is 0, 1 or 2;    Y is N or CH;    R3 and R4 are the same or different and are each independently selected from the group consisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, —OR7, —OAy, —C(O)R7, —C(O)Ay, —CO2R7, —CO2Ay, —SO2NHR9, —NR7R8, —NR7Ay, —NHHet, —NHR10Het, —R10cycloalkyl, —R10OR7, —R10OAy, —R10NR7R8 and —R10NR7Ay;    q is 0, 1, 2, 3, 4 or 5; and    each R5 is the same or different and is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —OR7, —OAy, —OHet, —OR10Ay, —OR10Het, —C(O)R9, —C(O)Ay, —C(O)Het, —CO2R9, —C(O)NR7R8, —C(O)NR7Ay, —C(O)NHR10Het, —C(S)NR9R11, —C(NH)NR7R8, —C(NH)NR7Ay, —S(O)nR9, —S(O)2NR7R8, —S(O)2NR7Ay, —NR7R8, —NR7Ay, —NHHet, —NHR10Ay, —NHR10Het, —R10cycloalkyl, —R10Het, —R10OR9, —R10C(O)R9, —R10CO2R9, —R10C(O)NR9R11, —R10C(O)NR7Ay, —R10C(O)NHR10Het, —R10C(S)NR9R11, —R10C(NH)NR9R11, —R10SO2R9, —R10SO2NR9R11, —R10SO2NHCOR9, —R10NR7R8, —R10NR7Ay, —R10NHC(NH)NR9R11, cyano, nitro and azido; or            two adjacent R5 groups together with the atoms to which they are bonded form a C5-6 cycloalkyl or aryl;wherein when Y is CH, R3 is not —NR7Ay.        
PCT Publication No. WO 91/00092 to SmithKline Beecham Corp. refers to imidazo[1,2-a]pyridine compounds of formula (I)
wherein:W1 is —(CR4R5)—(CR6R7)—, —CR5═CR7—, —N═CR7—, —S(O)m— or —O—; one of R1 and R0 is 4-pyridyl or C1-4alkyl-4-pyridyl, provided that when R1 is C1-4alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring, and the other of R1 and R0 is                (a) phenyl or monosubstituted phenyl wherein said substituent is C1-3alkylthio, C1-3alkylsulfinyl, C2-51-alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, C3-52-alkenyl-1-thio, C3-52alkenyl-1-sulfinyl, 1-acyloxy-1-alkylthio, C1-2alkoxy, halo, C1-4alkyl or Z wherein Z is —S—S—Z1 and Z1 is phenyl or C1-9alkyl; or        (b) disubstituted phenyl wherein said substituents are independently C1-3alkylthio, C1-2alkoxy, halo or C1-4alkyl; or        (c) disubstituted phenyl wherein one of said substituents is C1-3alkylsulfinyl, C2-51-alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, C3-52-alkenyl-1-thio, C3-52alkenyl-1-sulfinyl, or 1-acyloxy-1-alkylthio and the other is C1-2alkoxy, halo or C1-4alkyl; or        (d) disubstituted phenyl wherein the substituents are the same and are C1-3alkylsulfinyl, C2-51-alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, C3-52-alkenyl-1-thio, C3-52alkenyl-1-sulfinyl, or 1-acyloxy-1-alkylthio or wherein the substituents together form a methylene dioxy group; or        (e) monosubstituted phenyl wherein said substituent is        
t is 0 or 1; W1, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined herein;provided that:1) when W1 is —(CR4R5)—(CR6R7)— then                n is 0 or 1;        and R2, R3, R4, R5, R6, R7, R8 and R9 are independently —H or C1-2alkyl; and when R1 or R0 is 4-pyridyl, the other of R1 and R0 is other than mono-C1-2alkoxy-substituted phenyl or mono-halo-substituted phenyl; or        when n is 0, R4 and R5 together are oxo; R4 and R5 are both fluoro, or one of R4 and R5 is H and the other is OH;2) when W1 is —CR5═CR7— or —N═CR7— then        n is 1;        R3, R5, R7 and R9 are independently —H or C1-2alkyl; and        R2 and R8 together represent a double bond in the B ring such that the B ring is an aromatic pyridine or pyrimidine ring;3) when W1 is —S(O)m— then        m is 0, 1 or 2;        n is 1 or 2;        R3 and R9 are independently —H or C1-2alkyl;        R2 and R8 are independently —H or C1-2alkyl or R2 and R8 together represent a double bond in the B ring such that the B ring is an aromatic thiazole ring; further provided that:        (a) when R2 and R8 are independently —H or C1-2alkyl and R1 or R0 is 4-pyridyl, then the other of R1 and R0 is other than mono-C1-2alkoxy-substituted phenyl or mono-halo-substituted phenyl; and        (b) when R2 and R8 together represent a double bond in the B ring such that the B ring is an aromatic thiazole ring, the m is 0 and n is 1; and4) when W1 is —O— then        n is 1;        R3 and R9 are independently —H or C1-2alkyl; and        R2 and R8 together represent a double bond in the B ring such that the B ring is an aromatic oxazole ring;or a pharmaceutically acceptable salt thereoffor use in the inhibition of interleukin-1 and tumor necrosis factor production by monocytes and/or macrophages.        
PCT Publication No. WO 01/14375 to AstraZeneca AB relates to imidazo[1,2-a]pyridine and pyrazolo[2,3-a]pyridine derivatives of formula (I)
wherein Ring A is a imidazo[1,2-a]pyridine or pyrazolo[2,3-a]pyrid-3-yl; R2 is as defined therein, m is 0-5; wherein the values of R2 may be the same or different; R1 is as defined therein; n is 0 to 2, wherein the values of R1 may be the same or different; Ring B is phenyl or phenyl fused to a C5-7cycloalkyl ring; R3 is as defined therein; p is 0-4; wherein the values of R3 may be the same or different; R4 is as defined therein; q is 0-2; wherein the values of R4 may be the same or different; and wherein p+q≦5; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. The use of the compounds of formula (I) in the inhibition of cell cycle kinases CDK2, CDK4 and CDK6 are also described.